Lyme disease is an NIAID/NIH Group 1 Priority Emerging and Re-emerging Infectious Disease, and the most frequently reported arthropod-borne disease in the United States. Borrelia burgdorferi, the Lyme disease spirochete, can persistently infect humans for years. B. burgdorferi is often found in the connective tissues and associates with components of the extracellular matrix (ECM) such as fibronectin. Understanding the mechanisms behind borrellal adhesion to ECM components will permit the development of strategies to disrupt these interactions. Recently, we discovered that an antigenic outer surface lipoprotein, RevA, binds to fibronectin. We hypothesize that borrelial-ECM interactions, especially those mediated by fibronectin-binding proteins, are crucial for mammalian infection and persistence In the host. Studies are proposed to (1) Elucidate the mechanisms of RevA binding to fibronectin through site-directed mutagenesis of the RevA protein and analyses of specifically-bound fragments of fibronectin and (2) Characterize how RevA expression is regulated during the infection process, over time and in several tissues in the mouse model. PUBLIC HEALTH RELEVANCE: The bacterium which causes Lyme disease, Borrelia burgdorferi, can infect humans and other animals for years. Proteins on the outer surface of Borrelia play important roles in establishing infection in animals. Appreciating how these proteins are made and how they interact with the host will be an important step towards understanding the ability of this pathogen to infect humans. Data obtained in these studies will direct development of improved tools for treatment, prevention, and diagnosis of Lyme disease.